The reason that many anti-proliferative agents are effective orally but not topically in the treatment of psoriasis may be that they do not diffuse through skin to a sufficient extent to generate a clinically beneficial response. In order to test this hypothesis the synthesis and testing in animals of new types of S- and N- alkylated derivatives (prodrugs) of one member of the orally active, topically ineffective anti-proliferative agents (6-mercaptopurine (6-MP) and its riboside) is proposed. The prodrugs are designed to increase the delivery of 6-MP through skin. They are hydrolytically reversible derivatives that do not require any initial oxidative step to make them labile, and in that sense they may be considered as soft alkylated derivatives. Generally the soft alkylated derivatives of 6-MP have the formula RCOXCHR'X'-drug where X=N or O; X'=N or S; R is aryl, alkyl, alkoxy or alkylamino; and R' is hydrogen or an electron withdrawing functional group. Representative S-pivalyloxymethyl and N-methyl-N-carboethoxyaminomethyl derivatives of 6-MP and 6-MP riboside have been synthesized and characterized in terms of their hydrolysis rates, partition coefficients and ability to deliver 6-MP through skin in diffusion cell experiments. These soft alkylated derivatives regenerate 6-MP in vivo and have been found to increase the delivery of 6-MP across hairless mouse skin by 3 to 12 times. It is proposed that 1) the present derivatives be tested on hairless mice to determine if the derivatives inhibit DNA synthesis in hairless mice - an animal model that correlates well with topical clinical efficacy in man; 2) if the present derivatives are active, the rate of delivery of 6-MP be maximized by adjusting the R, X, X' and R' groups in the general formula to obtain the most favorable partition coefficient, diffusivity, and rate of regeneration of 6-MP for the derivatives; and 3) the best derivatives in terms of ability to deliver 6-MP be tested for inhibition of DNA synthesis in hairless mice. Thus, whether 6-MP is topically inactive or merely not enough 6-MP is getting through skin to be effective will be established in an animal model-hairless mice-that correlates with topical clinical efficacy in man. In addition, a potentially useful general approach (soft alkylated thiols and amines) to improving topical delivery and efficacy of anti-proliferative drugs will be optimized for one example, 6-MP.